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We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration., Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.

We present a theoretical model that demonstrates the integral role chromosome organization and structural mechanics play in the spreading of histone modifications involved in epigenetic regulation. Our model shows that heterogeneous nucleosome positioning, and the resulting position-dependent mechanical properties, must be included to reproduce several qualitative features of experimental data of histone methylation spreading around an artificially induced “nucleation site.” We show that our model recreates both the extent of spreading and the presence of a subdominant peak upstream of the transcription start site. Our model indicates that the spreading of epigenetic modifications is sensitive to heterogeneity in chromatin organization and the resulting variability in the chromatin’s mechanical properties, suggesting that nucleosome spacing can directly control the conferral of epigenetic marks by modifying the structural mechanics of the chromosome. It further illustrates how the physical organization of the DNA polymer may play a significant role in re-establishing the epigenetic code upon cell division.

The interaction of microbiota with its host has the ability to alter the cellular functions of both, through several mechanisms. Recent work, from many laboratories including our own, has shown that epigenetic mechanisms play an important role in the alteration of these cellular functions. Epigenetics broadly refers to change in the phenotype without a corresponding change in the DNA sequence. This change is usually brought by epigenetic modifications of the DNA itself, the histone proteins associated with the DNA in the chromatin, non-coding RNA or the modifications of the transcribed RNA. These modifications, also known as epigenetic code, do not change the DNA sequence but alter the expression level of specific genes. Microorganisms seem to have learned how to modify the host epigenetic code and modulate the host transcriptome in their favour. In this review, we explore the literature that describes the epigenetic interaction of bacteria, fungi and viruses, with their mammalian hosts.

Understanding how genes are expressed in the correct cell types and at the correct level is a key goal of developmental biology research. Gene regulation has traditionally been approached largely through observational methods, whereas perturbational approaches have lacked precision. CRISPR-Cas9 has begun to transform the study of gene regulation, allowing for precise manipulation of genomic sequences, epigenetic functionalization and gene expression. CRISPR-Cas9 technology has already led to the discovery of new paradigms in gene regulation and, as new CRISPR-based tools and methods continue to be developed, promises to transform our knowledge of the gene regulatory code and our ability to manipulate cell fate. Here, we discuss the current and future application of the emerging CRISPR toolbox toward predicting gene regulatory network behavior, improving stem cell disease modeling, dissecting the epigenetic code, reprogramming cell fate and treating diseases of gene dysregulation.

Evidence suggests that engineered nanomaterials (ENM) can induce epigenetic modifications. In this review, we provide an overview of the epigenetic modulation of gene expression induced by ENM used in a variety of applications: titanium dioxide (TiO2), silver (Ag), gold (Au), silica (SiO2) nanoparticles and carbon-based nanomaterials (CNM). Exposure to these ENM can trigger alterations in cell patterns of DNA methylation, post-transcriptional histone modifications and expression of non-coding RNA. Such effects are dependent on ENM dose and physicochemical properties including size, shape and surface chemistry, as well as on the cell/organism sensitivity. The genes affected are mostly involved in the regulation of the epigenetic machinery itself, as well as in apoptosis, cell cycle, DNA repair and inflammation related pathways, whose long-term alterations might lead to the onset or progression of certain pathologies. In addition, some DNA methylation patterns may be retained as a form of epigenetic memory. Prenatal exposure to ENM may impair the normal development of the offspring by transplacental effects and/or putative transmission of epimutations in imprinting genes. Thus, understanding the impact of ENM on the epigenome is of paramount importance and epigenetic evaluation must be considered when assessing the risk of ENM to human health. This work was supported by the NanoBioBarriers project (PTDC/MED‐TOX/31162/2017), co-financed by the Operational Program for Competitiveness and Internationalization (POCI) through European Regional Development Funds (FEDER/FNR) and through national funds by the Portuguese Foundation for Science and Technology (FCT). Thanks are also due to FCT/MCTES for the financial support to EPIUnit (info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04750/2020/PT).

The mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping., Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.

International audience; Neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer's disease (AD), are progressive conditions characterized by selective, disease-dependent loss of neuronal regions and/or subpopulations. Neuronal loss is preceded by a long period of neuronal dysfunction, during which glial cells also undergo major changes, including neuroinflammatory response. Those dramatic changes affecting both neuronal and glial cells associate with epigenetic and transcriptional dysregulations, characterized by defined cell-type-specific signatures. Notably, increasing studies support the view that altered regulation of transcriptional enhancers, which are distal regulatory regions of the genome capable of modulating the activity of promoters through chromatin looping, play a critical role in transcriptional dysregulation in HD and AD. We review current knowledge on enhancers in HD and AD, and highlight challenging issues to better decipher the epigenetic code of neurodegenerative diseases.

Background Transcription of genes residing within constitutive heterochromatin is paradoxical to the tenets of epigenetic code. The regulatory mechanisms of Drosophila melanogaster heterochromatic gene transcription remain largely unknown. Emerging evidence suggests that genome organization and transcriptional regulation are inter-linked. However, the pericentromeric genome organization is relatively less studied. Therefore, we sought to characterize the pericentromeric genome organization and understand how this organization along with the pericentromeric factors influences heterochromatic gene expression. Results Here, we characterized the pericentromeric genome organization in Drosophila melanogaster using 5C sequencing. Heterochromatic topologically associating domains (Het TADs) correlate with distinct epigenomic domains of active and repressed heterochromatic genes at the pericentromeres. These genes are known to depend on the heterochromatic landscape for their expression. However, HP1a or Su(var)3-9 RNAi has minimal effects on heterochromatic gene expression, despite causing significant changes in the global Het TAD organization. Probing further into this observation, we report the role of two other chromatin proteins enriched at the pericentromeres-dMES-4 and dADD1 in regulating the expression of a subset of heterochromatic genes. Conclusions Distinct pericentromeric genome organization and chromatin landscapes maintained by the interplay of heterochromatic factors (HP1a, H3K9me3, dMES-4 and dADD1) are sufficient to support heterochromatic gene expression despite the loss of global Het TAD structure. These findings open new avenues for future investigations into the mechanisms of heterochromatic gene expression.

During meiosis, homologous chromosomes pair and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, double-strand breaks (DSBs) initiate recombination within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have been identified. We identified Zcwpw1, containing H3K4me3 and H3K36me3 recognition domains, as having highly correlated expression with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognises CpG dinucleotides. Male Zcwpw1 knockout mice show completely normal DSB positioning, but persistent DMC1 foci, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest ZCWPW1 recognition of PRDM9-bound sites at DSB hotspots is critical for synapsis, and hence fertility., eLife digest Sexual reproduction – that is, the combination of sex cells from two different individuals to produce an embryo – is one of the many mechanisms that have evolved to maintain genetic diversity. Most human cells contain 23 pairs of chromosomes, with each chromosome in a pair carrying either a paternal or maternal copy of the same gene. To form an embryo with the right number of chromosomes, each sex cell (the egg or sperm cell) must only contain one chromosome from each pair. Sex cells are produced from parent cells containing two sets of paternal and maternal chromosomes: these cells then divide twice to form four sex cells which contain only one chromosome from each pair. Before the parent cell divides, a process known as ‘recombination’ takes place, which allows chromosomes in a pair to exchange bits of genetic information. This reshuffling ensures that each chromosome in a sex cell is unique. A protein called PRDM9 helps control which sections of genetic information are recombined by modifying proteins attached to the chromosomes, marking them as locations for exchange. The DNA at each of these sites is then broken and repaired using the genetic sequence of the chromosome it is paired with as a template, thus causing the two chromosomes to swap genes. In 2019, a group of researchers found a set of genes in the testis of mice that are expressed at the same time as the gene for PRDM9. This suggested that another protein called ZCWPW1 is likely involved in recombination, but the precise role of this protein was unclear. To answer this question, Wells, Bitoun et al. – including many of the researchers involved in the 2019 study – examined human cells grown in the laboratory to determine where ZCWPW1 binds to in the chromosome. This revealed that ZCWPW1 can be found at the same sites as PRDM9, which is responsible for bringing it there. Furthermore, cells from male mice lacking the gene for ZCWPW1 cannot complete the exchange of genetic information between chromosomes, meaning that the mice are infertile. As such, ZCWPW1 seems to connect location selection by PRDM9 to the DNA repair mechanisms needed for gene exchange between chromosomes. Infertility is a significant issue for humans affecting as many as one in every six couples. Fertility is complex and many of the biological mechanisms involved are not fully understood. This work suggests that both PRDM9 and ZCWPW1 are key to the production of sex cells and may be worth investigating as factors that affect fertility in humans.

Methylated non-CpGs (mCpHs) in mammalian cells yield weak enrichment signals and colocalize with methylated CpGs (mCpGs), thus have been considered byproducts of hyperactive methyltransferases. However, mCpHs are cell type-specific and associated with epigenetic regulation, although their dependency on mCpGs remains to be elucidated. In this study, we demonstrated that mCpHs colocalize with mCpGs in pluripotent stem cells, but not in brain cells. In addition, profiling genome-wide methylation patterns using a hidden Markov model revealed abundant genomic regions in which CpGs and CpHs are differentially methylated in brain. These regions were frequently located in putative enhancers, and mCpHs within the enhancers increased in correlation with brain age. The enhancers with hypermethylated CpHs were associated with genes functionally enriched in immune responses, and some of the genes were related to neuroinflammation and degeneration. This study provides insight into the roles of non-CpG methylation as an epigenetic code in the mammalian brain genome.

A wealth of studies over several decades has revealed an epigenetic prepattern that determines the competence of cellular differentiation in the developing liver. More recently, studies focused on the impact of epigenetic factors during liver regeneration suggest that an epigenetic code in the quiescent liver may establish its regenerative potential. We review work on the pioneer factors and other chromatin remodelers that impact the gene expression patterns instructing hepatocyte and biliary cell specification and differentiation, along with the requirement of epigenetic regulatory factors for hepatic outgrowth. We then explore recent studies involving the role of epigenetic regulators, Arid1a and Uhrf1, in efficient activation of proregenerative genes during liver regeneration, thus highlighting the epigenetic mechanisms of liver disease and tumor development.

We build a theoretical model of morphogenesis. This model describes cell fate in the developing organism using the notion of epigenetic code of each cell. Namely, given the epigenetic spectra of a cell and its neighboring cells, we can determine the corresponding cell event it will perform. This means that the properties of a group of cells (comprising an embryo or its part) at any time point are also known, and thus, the evolution of an embryo can be described. By this strategy, it is possible to establish the tissue, organ, or embryo shapes at any time, starting from a zygote. As an essential part of the model, the formalization of the notion of cell potency is introduced, and the related properties are discussed.

Diabetes is a chronic metabolic disorder that poses a global burden to healthcare. Increasing incidence of diabetes-related complications in the affected population includes a delay in wound healing that often results in non-traumatic limb amputations. Owing to the intricacies of the healing process and crosstalk between the multitude of participating cells, the identification of hyperglycaemia-induced changes at both cellular and molecular levels poses a challenge. Macrophages are one of the key participants in wound healing and continue to exert functional changes at the wound site since the time of injury. In the present review, we discuss the role of these cells and their aberrant functions in diabetic wounds. We have extensively studied the process of macrophage polarization (MP) and its modulation through epigenetic modifications. Data from both pre-clinical and clinical studies on diabetes have co-related hyperglycaemia induced changes in gene expression to an increased incidence of diabetic complications. Hyperglycaemia and oxidative stress, create an environment prone to changes in the epigenetic code, that is manifested as an altered inflammatory gene expression. Here, we have attempted to understand the different epigenetic modulations that possibly contribute towards dysregulated MP, resulting in delayed wound healing.

Epigenetics refers to functionally relevant genomic changes that do not involve changes in the basic nucleotide sequence. Majorly, these are of two types: DNA methylation and histone modifications. Small RNA molecules called miRNAs are often thought to mediate post-transcriptional epigenetic changes by mRNA degradation or translational attenuation. While DNA methylation and histone modifications have their own independent effects on various cellular events, several reports are suggestive of an obvious interplay between these phenomena and the miRNA regulatory program within the cell. Several miRNAs like miR-375, members of miR-29 family, miR-34, miR-200, and others are regulated by DNA methylation and histone modifications in various types of cancers and metabolic diseases. On the other hand, miRNAs like miR-449a, miR-148, miR-101, miR-214, and miR-128 target members of the epigenetic machinery and their dysregulation leads to diverse cellular aberrations. In spite of being independent cellular events, emergence of such reports that suggest a connection between DNA methylation, histone modification, and miRNA function in several diseases indicate that this connecting axis offers a valuable target with great therapeutic potential that might be exploited for disease management. We review the current status of crosstalk between the major epigenetic modifications and the miRNA machinery and discuss this in the context of health and disease.

Replication-coupled chromatin assembly is a very dynamic process that involves not only the replication fork machinery but also chromatin-related factors such as histones, histone chaperones, histone-modifying enzymes, and chromatin remodelers which ensure not only that the genetic information is properly replicated but also that the epigenetic code is reestablished in the daughter cell. Of the histone modifications associated with chromatin assembly, acetylation is the most abundant. Determining how newly synthesized histones get acetylated and what factors affect this modification is vital to understanding how cells manage to properly duplicate the epigenome. Here we describe a combination of the iPOND, quantitative mass spectrometry, and SILAC methodologies to study the protein composition of newly assembled chromatin and the modification state of the associated histones.

Cells are continuously subjected to an array of reactive/toxic chemical species which are produced both endogenously through metabolic pathways and taken up exogenously by diet and exposure to drugs or toxins. As a result, proteins often undergo non-enzymatic covalent modifications (NECMs) by these species, which can alter protein structure, function, stability, and binding partner affinity. NECMs accumulate over time and are linked to various diseases such as Alzheimer's disease, cancer, and diabetes. In the cellular proteome, histones have some of the longest half-lives, making them prime targets for NECMs. In addition, histones have emerged as key regulators of transcription, a function that is primarily controlled by modification of their tails. These modifications are usually installed or removed enzymatically, but recent evidence suggests that some may also occur non-enzymatically. Despite the vast knowledge detailing the relationship between histone modifications and gene regulation, NECMs on histones remain poorly explored. A major reason for this difference stems from the fact that, unlike their enzymatically installed counterparts, NECMs are difficult to both control and test in vivo. Here, we review advances in our understanding of the effect non-enzymatic covalent modifications (NECMs) have on the epigenetic landscape, cellular fate, and their implications in disease. Cumulatively, this illustrates how the epigenetic code is directly toxified by chemicals and detoxified by corresponding eraser enzymes.

Epigenetic modifications are important gene regulatory mechanisms conserved in plants, animals, and fungi. Chromatin reader domains are protein-protein/DNA interaction modules acting within the chromatin-modifying complex to function as molecular interpreters of the epigenetic code. Understanding how reader proteins recognize specific epigenetic modifications and mediate downstream chromatin and transcriptional events is fundamental to many biological processes. Recent studies have uncovered a number of novel reader proteins with diverse functions and mechanisms in plants. Here, we provide an overview of the recent progress on reader-mark recognition modes, the mechanisms by which reader proteins influence chromatin dynamics, and how reader-chromatin interactions regulate biological function. Because of space limitations, this review focuses on reader domains in plants that specifically bind histone methylation, histone acetylation, and DNA methylation.

Histone post-translational modification patterns represent epigenetic states of genomic genes and denote the state of their transcription, past history, and future potential in gene expression. Genome-wide chromatin modification patterns reported from various laboratories are assembled in the ENCODE database, providing a fertile ground for understanding epigenetic regulation of any genes of interest across many cell types. The IRF family genes critically control innate immunity as they direct expression and activities of interferons. While these genes have similar structural and functional traits, their chromatin landscapes and epigenetic features have not been systematically evaluated. Here, by mining ENCODE database using an imputational approach, we summarize chromatin modification patterns for 6 of 9 IRF genes and show characteristic features that connote their epigenetic states. BRD4 is a BET bromodomain protein that “reads and translates” epigenetic marks into transcription. We review recent findings that BRD4 controls constitutive and signal-dependent transcription of many genes, including IRF genes. BRD4 dynamically binds to various genomic genes with a spatial and temporal specificity. Of particular importance, BRD4 is shown to critically regulate IRF-dependent anti-pathogen protection, inflammatory responses triggered by NF-κB, and the growth and spread of many cancers. The advent of small molecule inhibitors that disrupt binding of BET bromdomain to acetylated histone marks has opened new therapeutic possibilities for cancer and inflammatory diseases.

Although the nature of the genetic control of adaptive behaviours in insects is a major unresolved problem it is now understood that epigenetic mechanisms, bound by genetic constraints, are prime drivers of brain plasticity arising from both developmental and experience-dependent events. With the recent advancements in methylomics and emerging analyses of histones and non-protein-coding RNAs, insect epigenetics is well positioned to ask more direct questions and importantly, address them experimentally. To achieve rapid progress, insect epigenetics needs to focus on mechanistic explanations of epigenomic dynamics and move beyond low-depth genome-wide analyses to cell-type specific epigenomics. One topic of a high priority is the impact of sequence variants on generating differential methylation patterns and their contribution to behavioural plasticity.

Cancer development is a complex process involving both genetic and epigenetic changes. Genetic changes in oncogenes and tumor-suppressor genes are generally considered as primary causes, since these genes may directly regulate cellular growth. In addition, it has been found that changes in epigenetic factors, through mutation or altered gene expression, may contribute to cancer development. In the nucleus of eukaryotic cells DNA and histone proteins form a structure called chromatin which consists of nucleosomes that, like beads on a string, are aligned along the DNA strand. Modifications in chromatin structure are essential for cell type-specific activation or repression of gene transcription, as well as other processes such as DNA repair, DNA replication and chromosome segregation. Alterations in epigenetic factors involved in chromatin dynamics may accelerate cell cycle progression and, ultimately, result in malignant transformation. Abnormal expression of remodeler and modifier enzymes, as well as histone variants, may confer to cancer cells the ability to reprogram their genomes and to yield, maintain or exacerbate malignant hallmarks. At the end, genetic and epigenetic alterations that are encountered in cancer cells may culminate in chromatin changes that may, by altering the quantity and quality of gene expression, promote cancer development. During the last decade a vast number of studies has uncovered epigenetic abnormalities that are associated with the (anomalous) packaging and remodeling of chromatin in cancer genomes. In this review I will focus on recently published work dealing with alterations in the primary structure of chromatin resulting from imprecise arrangements of nucleosomes along DNA, and its functional implications for cancer development. The primary chromatin structure is regulated by a variety of epigenetic mechanisms that may be deregulated through gene mutations and/or gene expression alterations. In recent years, it has become evident that changes in chromatin structure may coincide with the occurrence of cancer hallmarks. The functional interrelationships between such epigenetic alterations and cancer development are just becoming manifest and, therefore, the oncology community should continue to explore the molecular mechanisms governing the primary chromatin structure, both in normal and in cancer cells, in order to improve future approaches for cancer detection, prevention and therapy, as also for circumventing drug resistance.

Epigenetic modifying factors are fundamental regulators of chromatin structure and gene expression during development and differentiation through the induction of chemical modifications on histones, DNA or via remodeling of the chromatin structure. Protein complexes involved in these three processes contain non-canonical RNA-binding components that interact with long non-coding RNAs, in many cases in the absence of any sequence or structural signatures. However, there is growing evidence of the role of such protein-lncRNA interactions in the regulation of the epigenetic landscape in vivo. This review summarizes the growing number of epigenetic modifying factors described to interact with lncRNAs in mouse and human, and then discusses the challenges that lay ahead in understanding lncRNAs as part of the intricate networks of epigenetic regulation. A combination of protein and RNA-centric approaches is required for this purpose. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.

The bromodomain family of proteins are 'readers' of acetylated lysines of histones, a key mark in the epigenetic code of gene regulation. Without high quality chemical probes with which to study these proteins, their biological function, and potential use in therapeutics, remains unknown. Recently, a number of chemical ligands were reported for the previously unprobed bromodomain proteins BRD7 and BRD9. Herein the development and characterisation of probes against these proteins is detailed, including the preliminary biological activity of BRD7 and BRD9 assessed using these probes. Future studies utilising these chemically-diverse compounds in parallel will allow for a confident assessment of the role of BRD7/9, and give multiple entry points into any subsequent pharmaceutical programs.

Rationale: Epigenetic mechanisms are crucial for cell identity and transcriptional control. The heart consists of different cell types, including cardiac myocytes, endothelial cells, fibroblasts, and others. Therefore, cell type–specific analysis is needed to gain mechanistic insight into the regulation of gene expression in cardiac myocytes. Although cytosolic mRNA represents steady-state levels, nuclear mRNA more closely reflects transcriptional activity. To unravel epigenetic mechanisms of transcriptional control, cell type–specific analysis of nuclear mRNA and epigenetic modifications is crucial. Objective: The aim was to purify cardiac myocyte nuclei from hearts of different species by magnetic- or fluorescent-assisted sorting and to determine the nuclear and cellular RNA expression profiles and epigenetic marks in a cardiac myocyte–specific manner. Methods and Results: Frozen cardiac tissue samples were used to isolate cardiac myocyte nuclei. High sorting purity was confirmed for cardiac myocyte nuclei isolated from mice, rats, and humans. Deep sequencing of nuclear RNA revealed a major fraction of nascent, unspliced RNA in contrast to results obtained from purified cardiac myocytes. Cardiac myocyte nuclear and cellular RNA expression profiles showed differences, especially for metabolic genes. Genome-wide maps of the transcriptional elongation mark H3K36me3 were generated by chromatin-immunoprecipitation. Transcriptome and epigenetic data confirmed the high degree of cardiac myocyte–specificity of our protocol. An integrative analysis of nuclear mRNA and histone mark occurrence indicated a major impact of the chromatin state on transcriptional activity in cardiac myocytes. Conclusions: This study establishes cardiac myocyte–specific sorting of nuclei as a universal method to investigate epigenetic and transcriptional processes in cardiac myocytes of different origins. These data sets provide novel insight into cardiac myocyte transcription.

Background and aims Epithelial-to-mesenchymal transition (EMT) and the reverse mesenchymal-to-epithelial transition (MET) are manifestations of cellular plasticity that imply a dynamic and profound gene expression reprogramming. While a major epigenetic code controlling the coordinated regulation of a whole transcriptional profile is guaranteed by DNA methylation, DNA methyltransferase (DNMT) activities in EMT/MET dynamics are still largely unexplored. Here, we investigated the molecular mechanisms directly linking HNF4α, the master effector of MET, to the regulation of both de novo of DNMT 3A and 3B. Methods Correlation among EMT/MET markers, microRNA29 and DNMT3s expression was evaluated by RT-qPCR, Western blotting and immunocytochemical analysis. Functional roles of microRNAs and DNMT3s were tested by anti-miRs, microRNA precursors and chemical inhibitors. ChIP was utilized for investigating HNF4α DNA binding activity. Results HNF4α silencing was sufficient to induce positive modulation of DNMT3B, in in vitro differentiated hepatocytes as well as in vivo hepatocyte-specific Hnf4α knockout mice, and DNMT3A, in vitro, but not DNMT1. In exploring the molecular mechanisms underlying these observations, evidence have been gathered for (i) the inverse correlation between DNMT3 levels and the expression of their regulators miR-29a and miR-29b and (ii) the role of HNF4α as a direct regulator of miR-29a-b transcription. Notably, during TGFβ-induced EMT, DNMT3s' pivotal function has been proved, thus suggesting the need for the repression of these DNMTs in the maintenance of a differentiated phenotype. Conclusions HNF4α maintains hepatocyte identity by regulating miR-29a and -29b expression, which in turn control epigenetic modifications by limiting DNMT3A and DNMT3B levels.

After the study of the gene code as a trigger for obesity, epigenetic code has appeared as a novel tool in the diagnosis, prognosis and treatment of obesity, and its related comorbidities. This review summarizes the status of the epigenetic field associated with obesity, and the current epigenetic-based approaches for obesity treatment.Thanks to technical advances, novel and key obesity-associated polymorphisms have been described by genome-wide association studies, but there are limitations with their predictive power. Epigenetics is also studied for disease association, which involves decoding of the genome information, transcriptional status and later phenotypes. Obesity could be induced during adult life by feeding and other environmental factors, and there is a strong association between obesity features and specific epigenetic patterns. These patterns could be established during early life stages, and programme the risk of obesity and its comorbidities during adult life. Furthermore, recent studies have shown that DNA methylation profile could be applied as biomarkers of diet-induced weight loss treatment.High-throughput technologies, recently implemented for commercial genetic test panels, could soon lead to the creation of epigenetic test panels for obesity. Nonetheless, epigenetics is a modifiable risk factor, and different dietary patterns or environmental insights during distinct stages of life could lead to rewriting of the epigenetic profile.

Members of the INhibitor of Growth (ING) family of proteins act as readers of the epigenetic code through specific recognition of the trimethylated form of lysine 4 of histone H3 (H3K4Me3) by their plant homeodomains. The founding member of the family, ING1, was initially identified as a tumor suppressor with altered regulation in a variety of cancer types. While alterations in ING1 and ING4 levels have been reported in a variety of cancer types, little is known regarding ING3 protein levels in normal or transformed cells due to a lack of reliable immunological tools. In this study we present the characterization of a new monoclonal antibody we have developed against ING3 that specifically recognizes human and mouse ING3. The antibody works in western blots, immunofluorescence, immunoprecipitation and immunohistochemistry. Using this antibody we show that ING3 is most highly expressed in small intestine, bone marrow and epidermis, tissues in which cells undergo rapid proliferation and renewal. Consistent with this observation, we show that ING3 is expressed at significantly higher levels in proliferating versus quiescent epithelial cells. These data suggest that ING3 levels may serve as a surrogate for growth rate, and suggest possible roles for ING3 in growth and self renewal and related diseases such as cancer.

In a eukaryotic cell, the transcriptional fate of a gene is determined by the profile of the epigenetic modifications it is associated with and the conformation it adopts within the chromatin. Therefore, the function that a cell performs is dictated by the sum total of the chromatin organization and the associated epigenetic modifications of each individual gene in the genome (epigenome). As the function of a cell during development and differentiation is determined by its microenvironment, any factor that can alter this microenvironment should be able to alter the epigenome of a cell. In the study published in Nature Communications (Yaseen [2015] Nature Communications 6:8922 doi: 10.1038/ncomms9922), we show that pathogenic Mycobacterium tuberculosis has evolved strategies to exploit this pliability of the host epigenome for its own survival. We describe the identification of a methyltransferase from M. tuberculosis that functions to modulate the host epigenome by methylating a novel, non-canonical arginine, H3R42 in histone H3. In another study, we showed that the mycobacterial protein Rv2966c methylates cytosines present in non-CpG context within host genomic DNA upon infection. Proteins with ability to directly methylate host histones H3 at a novel lysine residue (H3K14) has also been identified from Legionella pnemophilia (RomA). All these studies indicate the use of non-canonical epigenetic mechanisms by pathogenic bacteria to hijack the host transcriptional machinery.

The central dogma of gene expression entails the flow of genetic information from DNA to RNA, then to protein. Decades of studies on epigenetics have characterized an additional layer of information, where epigenetic states help to shape differential utilization of genetic information. Orchestrating conditional gene expressions to elicit a defined phenotype and function, epigenetics states distinguish different cell types or maintain a long-lived memory of past signals. Packaging the genetic information in the nucleus of the eukaryotic cell, chromatin provides a large regulatory repertoire that capacitates the genome to give rise to many distinct epigenomes. We will discuss how reversible, heritable functional annotation mechanisms in chromatin may have evolved from basic chemical diversification of the underlying molecules.

International audience; DNA methylation is an essential epigenetic modification, present in both unique DNA sequences and repetitive elements, but its exact function in repetitive elements remains obscure. Here, we describe the genome-wide comparative analysis of the 5mC, 5hmC, 5fC, and 5caC profiles of repetitive elements in mouse embryonic fibroblasts and mouse embryonic stem cells. We provide evidence for distinct and highly specific DNA methylation/oxidation patterns of the repetitive elements in both cell types, which mainly affect CA repeats and evolutionarily conserved mouse-specific transposable elements including IAP-LTRs, SINEs B1m/B2m, and L1Md-LINEs. DNA methylation controls the expression of these retroelements, which are clustered at specific locations in the mouse genome. We show that TDG is implicated in the regulation of their unique DNA methylation/oxidation signatures and their dynamics. Our data suggest the existence of a novel epigenetic code for the most recently acquired evolutionarily conserved repeats that could play a major role in cell differentiation.

To study the impact of epigenetic changes on biological functions, the ability to manipulate the epigenetic status of certain genomic regions artificially could be an indispensable technology. "Epigenome editing" techniques have gradually emerged that apply TALE or CRISPR/Cas9 technologies with various effector domains isolated from epigenetic code writers or erasers such as DNA methyltransferase, 5-methylcytosine oxidase, and histone modification enzymes. Here we demonstrate that a TALE recognizing a major satellite, consisting of a repeated sequence in pericentromeres, could be fused with the bacterial CpG methyltransferase, SssI. ChIP-qPCR assays demonstrated that the fusion protein TALMaj-SssI preferentially bound to major chromosomal satellites in cultured cell lines. Then, TALMaj-SssI was expressed in fertilized mouse oocytes with hypomethylated major satellites (10-20% CpG islands). Bisulfite sequencing revealed that the DNA methylation status was increased specifically in major satellites (50-60%), but not in minor satellites or other repeat elements, such as Intracisternal A-particle (IAP) or long interspersed nuclear elements-1 (Line1) when the expression level of TALMaj-SssI is optimized in the cell. At a microscopic level, distal ends of chromosomes at the first mitotic stage were dramatically highlighted by the mCherry-tagged methyl CpG binding domain of human MBD1 (mCherry-MBD-NLS). Moreover, targeted DNA methylation to major satellites did not interfere with kinetochore function during early embryonic cleavages. Co-injection of dCas9 fused with SssI and guide RNA (gRNA) recognizing major satellite sequences enabled increment of the DNA methylation in the satellites, but a few off-target effects were also observed in minor satellites and retrotransposons. Although CRISPR can be applied instead of the TALE system, technical improvements to reduce off-target effects are required. We have demonstrated a new method of introducing DNA methylation without the need of other binding partners using the CpG methyltransferase, SssI.

In this review, the sugar portions of glycoproteins, glycolipids, and glycosaminoglycans constitute the glycome, and the genes involved in their biosynthesis, degradation, transport and recognition are referred to as "glycogenes". The extreme complexity of the glycome requires the regulatory layer to be provided by the epigenetic mechanisms. Almost all types of cancers present glycosylation aberrations, giving rise to phenotypic changes and to the expression of tumor markers. In this review, we discuss how cancer-associated alterations of promoter methylation, histone methylation/acetylation, and miRNAs determine glycomic changes associated with the malignant phenotype. Usually, increased promoter methylation and miRNA expression induce glycogene silencing. However, treatment with demethylating agents sometimes results in silencing, rather than in a reactivation of glycogenes, suggesting the involvement of distant methylation-dependent regulatory elements. From a therapeutic perspective aimed at the normalization of the malignant glycome, it appears that miRNA targeting of cancer-deranged glycogenes can be a more specific and promising approach than the use of drugs, which broad target methylation/acetylation. A very specific type of glycosylation, the addition of GlcNAc to serine or threonine (O-GlcNAc), is not only regulated by epigenetic mechanisms, but is an epigenetic modifier of histones and transcription factors. Thus, glycosylation is both under the control of epigenetic mechanisms and is an integral part of the epigenetic code.

Accumulated findings have demonstrated that the epigenetic code provides a potential link between prenatal stress and changes in gene expression that could be involved in the developmental programming of various chronic diseases in later life. Meanwhile, based on the fact that epigenetic modifications are reversible and can be manipulated, this provides a unique chance to develop multiple novel epigenetic-based therapeutic strategies against many chronic diseases in early developmental periods. This article will give a short review of recent findings of prenatal insult-induced epigenetic changes in developmental origins of several chronic diseases, and will attempt to provide an overview of the current epigenetic-based strategies applied in the early prevention, diagnosis and possible therapies for human chronic diseases.

The multiple lineages and differentiation states that constitute the T-cell compartment all derive from a common thymic precursor. These distinct transcriptional states are maintained both in time and after multiple rounds of cell division by the concerted actions of a small set of lineage-defining transcription factors that act in conjunction with a suite of chromatin-modifying enzymes to activate, repress, and fine-tune gene expression. These chromatin modifications collectively provide an epigenetic code that allows the stable and heritable maintenance of the T-cell phenotype. Recently, it has become apparent that the epigenetic code represents a therapeutic target for a variety of immune cell disorders, including lymphoma and acute and chronic inflammatory diseases. Here, we review the recent advances in epigenetic regulation of gene expression, particularly as it relates to the T-cell differentiation and function.

The precise, temporal order of gene expression during development is critical to ensure proper lineage commitment, cell fate determination, and ultimately, organogenesis. Epigenetic regulation of chromatin structure is fundamental to the activation or repression of genes during embryonic development. In recent years, there has been an explosion of research relating to various modes of epigenetic regulation, such as DNA methylation, post-translational histone tail modifications, noncoding RNA control of chromatin structure, and nucleosome remodeling. Technological advances in genome-wide epigenetic profiling and pluripotent stem cell differentiation have been primary drivers for elucidating the epigenetic control of cellular identity during development and nuclear reprogramming. Not only do epigenetic mechanisms regulate transcriptional states in a cell-type–specific manner but also they establish higher order genomic topology and nuclear architecture. Here, we review the epigenetic control of pluripotency and changes associated with pluripotent stem cell differentiation. We focus on DNA methylation, DNA demethylation, and common histone tail modifications. Finally, we briefly discuss epigenetic heterogeneity among pluripotent stem cell lines and the influence of epigenetic patterns on genome topology.

The mammalian genome is packaged into chromatin that is further compacted into three-dimensional structures consisting of distinct functional domains. The higher order structure of chromatin is in part dictated by enzymatic DNA methylation and histone modifications to establish epigenetic layers controlling gene expression and cellular functions, without altering the underlying DNA sequences. Apart from DNA and histone modifications, non-coding RNAs can also regulate the dynamics of the mammalian gene expression and various physiological functions including cell division, differentiation, and apoptosis. Aberrant epigenetic signatures are associated with abnormal developmental processes and diseases such as cancer. In this review, we will discuss the different layers of epigenetic regulation, including writer enzymes for DNA methylation, histone modifications, non-coding RNA, and chromatin conformation. We will highlight the combinatorial role of these structural and chemical modifications along with their partners in various cellular processes in mammalian cells. We will also address the cis and trans interacting "reader" proteins that recognize these modifications and "eraser" enzymes that remove these marks. Furthermore, an attempt will be made to discuss the interplay between various epigenetic writers, readers, and erasures in the establishment of mammalian epigenetic mechanisms.

The emergence of long non-coding RNAs (lncRNAs) has shaken up our conception of gene expression regulation, as lncRNAs take prominent positions as components of cellular networks. Several cellular processes involve lncRNAs, and a significant number of them have been shown to function in cooperation with chromatin modifying enzymes to promote epigenetic activation or silencing of gene expression. Different model mechanisms have been proposed to explain how lncRNAs achieve regulation of gene expression by interacting with the epigenetic machinery. Here we describe these models in light of the current knowledge of lncRNAs, such as Xist and HOTAIR, and discuss recent literature on the role of the three-dimensional structure of the genome in the mechanism of action of lncRNAs and chromatin modifiers.

Long-term hematopoietic stem cells (HSCs) are capable of self-renewal and differentiation into all mature hematopoietic lineages. This process is regulated by transcription factors interact with co-factors to orchestrate chromatin structure and facilitate gene expression. To generate a compendium of factors that establish the epigenetic code in HSCs, we have undertaken the first large-scale in vivo reverse genetic screen targeting chromatin factors. We have designed and injected antisense morpholinos to knockdown expression of 488 zebrafish orthologs of conserved human chromatin factors. The resultant morphants were analyzed by whole embryo in situ hybridization at 36 hours post fertilization for expression of two HSC marker genes, c-myb and runx1, which are expressed in the developing blood stem cells. Morphants were categorized into five groups based on HSC marker expression, ranging from no change to mild, intermediate, or strong reduction in expression or an increase in expression. 29 morpholinos caused a complete or near complete knockdown of HSC marker expression, while 4 were found to increase HSC marker expression. As ubiquitous knockdown of chromatin factors could interfere with vascular development and the establishment of proper arterial identity, a crucial upstream event for HSC formation, we subsequently analyzed morphants with the most robust HSC phenotypes using two vascular markers: kdr for overall vasculogenesis and ephrinb2a for arterial formation. We found that of the 29 morpholinos that caused reduced marker expression, only 9 showed reduced overall vascular or arterial marker staining, suggesting that the majority of morphants with HSC phenotypes are specific to HSC formation. For the 4 morphants with increased HSC marker expression, vasculature appeared normal. These factors likely function as potent negative regulators of HSC development. Several genes known to be essential for HSC self-renewal and maintenance were identified in the screen. For example, knockdown of Mll or Dot1, which are also present in leukemia fusion proteins, fail to specify HSCs, as indicated by a nearly complete reduction in expression of the HSC markers in embryos tested. Of the remaining hits, many represent factors with no previous function ascribed in hematopoiesis. By incorporating protein interaction data, we have defined a handful of complexes necessary for HSC specification, including the SWI/SNF, ISWI, SET1/MLL, CBP/P300/HBO1/NuA4, HDAC/NuRD, and Polycomb complexes. As chromatin factors associated with the same complex likely share target binding sites, we analyzed 34 published ChIP-seq datasets in K562 erythroleukemia cells of chromatin factors tested in the screen, including hits from our screen: SIN3A, CHD4, HDAC1, TAF1, and JARID1C associated with the HDAC/NuRD complex and RNF2, SUZ12, CBX2, and CBX8 from the Polycomb complexes. We ranked triplet combinations of these factors together with all other groups of three factors based on the percent overlap of target genes. The HDAC/NuRD and PRC1/2 complex combinations predicted from our screen fell within the top 20% of all possible combinations of 3 factors, suggesting that our screen has identified chromatin factors that function in distinct complexes to regulate hematopoietic development. Our work has been compiled into a web-based database that will be made publicly available upon publication. Within this database, users can search by gene names and aliases, chromatin domain names and human or zebrafish genes. All experimental data, including experimental design, materials, protocols, images, and all further analyses of the 33 most robust morphants is included. Our large-scale genetic analysis of chromatin factors involved in HSC development provides a comprehensive view of the programs involved in epigenetic regulation of the blood program, offering new avenues to pursue in the study of histone modifications in HSCs and for therapeutic alternatives for patients with blood disorders and leukemia. Disclosures: Zon: FATE Therapeutics, Inc: Consultancy, Equity Ownership, Founder Other, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties; Stemgent, Inc: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Stocks, Stocks Other; Scholar Rock: Consultancy, Equity Ownership, Founder, Founder Other, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.

To improve light propagation through the retina, the rod nuclei of nocturnal mammals are uniquely changed compared to the nuclei of other cells. In particular, the main classes of chromatin are segregated in them and form regular concentric shells in order; inverted in comparison to conventional nuclei. A broad study of the epigenetic landscape of the inverted and conventional mouse retinal nuclei indicated several differences between them and several features of general interest for the organization of the mammalian nuclei. In difference to nuclei with conventional architecture, the packing density of pericentromeric satellites and LINE-rich chromatin is similar in inverted rod nuclei; euchromatin has a lower packing density in both cases. A high global chromatin condensation in rod nuclei minimizes the structural difference between active and inactive X chromosome homologues. DNA methylation is observed primarily in the chromocenter, Dnmt1 is primarily associated with the euchromatic shell. Heterochromatin proteins HP1-alpha and HP1-beta localize in heterochromatic shells, whereas HP1-gamma is associated with euchromatin. For most of the 25 studied histone modifications, we observed predominant colocalization with a certain main chromatin class. Both inversions in rod nuclei and maintenance of peripheral heterochromatin in conventional nuclei are not affected by a loss or depletion of the major silencing core histone modifications in respective knock-out mice, but for different reasons. Maintenance of peripheral heterochromatin appears to be ensured by redundancy both at the level of enzymes setting the epigenetic code (writers) and the code itself, whereas inversion in rods rely on the absence of the peripheral heterochromatin tethers (absence of code readers).

Fertilization is a very dynamic period of comprehensive chromatin remodeling, from which two specialized cells result in a totipotent zygote. The formation of a totipotent cell requires extensive epigenetic remodeling that, although independent of modifications in the DNA sequence, still entails a profound cell-fate change, supported by transcriptional profile modifications. As a result of finely tuned interactions between numerous mechanisms, the goal of fertilization is to form a full healthy new individual. To avoid the persistence of alterations in epigenetic marks, the epigenetic information contained in each gamete is reset during early embryogenesis. Covalent modification of DNA by methylation, as well as posttranslational modifications of histone proteins and noncoding RNAs, appears to be the main epigenetic mechanisms that control gene expression. These allow different cells in an organism to express different transcription profiles, despite each cell containing the same DNA sequence. In the context of replacement of spermatic protamine with histones from the oocyte, active cell division, and specification of different lineages, active and passive mechanisms of epigenetic remodeling have been revealed as critical for editing the epigenetic profile of the early embryo. Importantly, redundant factors and mechanisms are likely in place, and only a few have been reported as critical for fertilization or embryo survival by the use of knockout models. The aim of this review is to highlight the main mechanisms of epigenetic remodeling that ensue after fertilization in mammals.

Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins offer a breakthrough platform for cheap, programmable, and effective sequence-specific DNA targeting. The CRISPR-Cas system is naturally equipped for targeted DNA cutting through its native nuclease activity. As such, groups researching a broad spectrum of biological organisms have quickly adopted the technology with groundbreaking applications to genomic sequence editing in over 20 different species. However, the biological code of life is not only encoded in genetics but also in epigenetics as well. While genetic sequence editing is a powerful ability, we must also be able to edit and regulate transcriptional and epigenetic code. Taking inspiration from work on earlier sequence-specific targeting technologies such as zinc fingers (ZFs) and transcription activator-like effectors (TALEs), researchers quickly expanded the CRISPR-Cas toolbox to include transcriptional activation, repression, and epigenetic modification. In this review, we highlight advances that extend the CRISPR-Cas toolkit for transcriptional and epigenetic regulation, as well as best practice guidelines for these tools, and a perspective on future applications.

The epigenomic era has revealed a well-connected network of molecular processes that shape the chromatin landscape. These processes comprise abnormal methylomes, transcriptosomes, genome-wide histone post-transcriptional modifications patterns, histone variants, and noncoding RNAs. The mapping of these processes in large scale by chromatin immunoprecipitation sequencing and other methodologies in both cancer and normal cells reveals novel therapeutic opportunities for anticancer intervention. The goal of this minireview is to summarize pharmacological strategies to modify the epigenetic landscape of cancer cells. These approaches include the use of novel small molecule inhibitors of epigenetic processes specifically deregulated in cancer cells and the design of engineered proteins able to stably reprogram the epigenetic code in cancer cells in a way that is similar to normal cells.

Epigenetic marks in an organism can be altered by environmental factors throughout life. Although changes in the epigenetic code can be positive, some are associated with severe diseases, in particular, cancer and neuropsychiatric disorders. Recent evidence has indicated that certain epigenetic marks can be inherited, and reshape developmental and cellular features over generations. This review examines the challenging possibility that epigenetic changes induced by environmental factors can contribute to some of the inheritance of disease and disease risk. This concept has immense implications for the understanding of biological functions and disease etiology, and provides potential novel strategies for diagnosis and treatment. Examples of epigenetic inheritance relevant to human disease, such as the detrimental effects of traumatic stress or drug/toxic exposure on brain functions, are reviewed. Different possible routes of transmission of epigenetic information involving the germline or germline-independent transfer are discussed, and different mechanisms for the maintenance and transmission of epigenetic information like chromatin remodeling and small noncoding RNAs are considered. Future research directions and remaining major challenges in this field are also outlined. Finally, the adaptive value of epigenetic inheritance, and the cost and benefit of allowing acquired epigenetic marks to persist across generations is critically evaluated.

Through epigenetic modifications, specific long-term phenotypic consequences can arise from environmental influence on slowly evolving genomic DNA. Heritable epigenetic information regulates nucleosomal arrangement around DNA and determines patterns of gene silencing or active transcription. One of the greatest challenges in the study of epigenetics as it relates to disease is the enormous diversity of proteins, histone modifications and DNA methylation patterns associated with each unique maladaptive phenotype. This is further complicated by a limitless combination of environmental cues that could alter the epigenome of specific cell types, tissues, organs and systems. In addition, complexities arise from the interpretation of studies describing analogous but not identical processes in flies, plants, worms, yeast, ciliated protozoans, tumor cells and mammals. This review integrates fundamental basic concepts of epigenetics with specific focus on how the epigenetic machinery interacts and operates in continuity to silence or activate gene expression. Topics covered include the connection between DNA methylation, methyl-CpG-binding proteins, transcriptional repression complexes, histone residues, histone modifications that mediate gene repression or relaxation, histone core variant stability, H1 histone linker flexibility, FACT complex, nucleosomal remodeling complexes, HP1 and nuclear lamins.

Genomic imprinting is an epigenetic process leading to parental-specific expression of one to two percent of mammalian genes that offers one of the best model systems for a molecular analysis of epigenetic regulation in development and disease. In the twenty years since the first imprinted gene was identified, this model has had a significant impact on decoding epigenetic information in mammals. So far it has led to the discovery of long-range cis-acting control elements whose epigenetic state regulates small clusters of genes and of unusual macro noncoding RNAs (ncRNAs) that directly repress genes in cis, and critically, it has demonstrated that one biological role of DNA methylation is to allow expression of genes normally repressed by default. This review describes the progress in understanding how imprinted protein-coding genes are silenced; in particular, it focuses on the role of macro ncRNAs that have broad relevance as a potential new layer of regulatory information in the mammalian genome.

Although all nucleated cells within a multicellular organism contain a complete copy of the genome, cell identity relies on the expression of a specific subset of genes. Therefore, when cells divide they must not only copy their genome to their daughters, but also ensure that the pattern of gene expression present before division is restored. While the carrier of this epigenetic memory has been a topic of much research and debate, post-translational modifications of histone proteins have emerged in the vanguard of candidates. In this paper we examine the mechanisms by which histone post-translational modifications are propagated through DNA replication and cell division, and we critically examine the evidence that they can also act as vectors of epigenetic memory. Finally, we consider ways in which epigenetic memory might be disrupted by interfering with the mechanisms of DNA replication.

Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in post-mitotic neurons as a means of consolidating, and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an “epigenetic code” in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation, and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.

High-throughput genomic sequencing and quantitative mass spectrometry (MS)-based proteomics technology have recently emerged as powerful tools, increasing our understanding of chromatin structure and function. Both of these approaches require substantial investments and expertise in terms of instrumentation, experimental methodology, bioinformatics, and data interpretation and are, therefore, usually applied independently from each other by dedicated research groups. However, when applied reiteratively in the context of epigenetics research these approaches are strongly synergistic in nature.

It is generally agreed that adipocytes originate from mesenchymal stem cells in what can be divided into two processes: determination and differentiation. In the past decade, many factors associated with epigenetic signals have been proved to be pivotal for the appropriate timing of adipogenesis progression. A large number of coregulators at critical gene promoters set up specific patterns of DNA methylation, histone acetylation and methylation, and nucleosome rearrangement, that act as an epigenetic code to modulate the correct progress of adipocyte differentiation and adipogenesis during adipogenesis. In this review, we focus on the functions and roles of epigenetic processes in preadipocyte differentiation and adipogenesis.

An epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Epigenetic modifications such as DNA methylation, together with covalent modification of histones, are thought to alter chromatin density and accessibility of the DNA to cellular machinery, thereby modulating the transcriptional potential of the underlying DNA sequence. As environmental changes influence epigenetic marks, epigenetics provides an added layer of variation that might mediate the relationship between genotype and internal and external environmental factors. Integration of our knowledge in genetics, epigenomics, and genomics with the use of systems biology tools may present investigators with new, powerful tools to study many complex human diseases such as kidney disease.